Polycystic kidney disease (PKD) is a prevalent inherited disease in humans with a frequency of about 1 in 500. Adult PKD (ADPKD) is an autosomal dominant disorder affecting approximately 500,000 Americans with about 7,000 new patients identified each year. Infants with autosomal recessive (AR) PKD inherit a rapidly developing form, which can lead to renal insufficiency in the neonatal period.
The disease is characterized by the proliferation of epithelial cells, formation of renal cysts, liver cysts, intracranial aneurysm, and progression of renal insufficiency. PKD1, the gene that is mutated in approximately 85% of autosomal dominant polycystic kidney disease (ADPKD) cases in humans, has recently been identified (The European Polycystic Kidney Disease Consortium, 1994). Most mutations identified in affected families appear to be inactivating for the PKD1 and PKD2 genes. Recent evidence has suggested that a two-hit mechanism, in which the normal PKD1 allele is also inactivated, may be required for cyst growth.
The large number of genes showing abnormal expression in cystic kidneys from humans and rodents with PKD suggests that cellular processes associated with signal transduction, transcriptional regulation, and cell-cycle control are involved in cyst formation and that the cellular defect in PKD directly affects the regulation of epithelial differentiation (Calvet, 1998; Torres, 1998).
The role of c-myc in cystogenesis in the kidney and a correlation between high c-myc expression and PKD has been established. Rodent models are available to test possible therapeutic agents for efficacy against PKD (Calvet, 1998). These models take advantage of naturally occurring mutations, which confer the ARPKD and ADPKD phenotypes. The C57BL/6J-cpk/cpk mouse is a model of human ARPKD with similar renal pathology to that observed in human disease.
An approach to treating PKD based on the role of c-myc in the disease would therefore be highly desirable. To minimize complications, this approach should be efficacious in modulating the symptoms of PKD, easy to administer and without significant side effects.